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We aimed to investigate whether immunohistochemistry (IHC) can be used to identify <jats:italic>CCNE1<\/jats:italic> amplification status and to validate whether <jats:italic>CCNE1<\/jats:italic> high\u2010level amplification and overexpression are prognostic in HGSC. A testing set of 528 HGSC samples stained with two optimised IHC assays (clones EP126 and HE12) was subjected to digital image analysis and visual scoring. DNA and RNA chromogenic <jats:italic>in situ<\/jats:italic> hybridisation for <jats:italic>CCNE1<\/jats:italic> were performed. IHC cut\u2010off was determined by receiver operating characteristics (ROC). Survival analyses (endpoint ovarian cancer specific survival) were performed and validated in an independent validation set of 764 HGSC. Finally, combined amplification\/expression status was evaluated in cases with complete data (<jats:italic>n<\/jats:italic> = 1114). <jats:italic>CCNE1<\/jats:italic> high\u2010level amplification was present in 11.2% of patients in the testing set and 10.2% in the combined cohort. The optimal cut\u2010off for IHC to predict <jats:italic>CCNE1<\/jats:italic> high\u2010level amplification was 60% positive tumour cells with at least 5% strong staining cells (sensitivity 81.6%, specificity 77.4%). <jats:italic>CCNE1<\/jats:italic> high\u2010level amplification and overexpression were associated with survival in the testing and validation set. Combined <jats:italic>CCNE1<\/jats:italic> high\u2010level amplification and overexpression was present in 8.3% of patients, mutually exclusive to germline <jats:italic>BRCA1\/2<\/jats:italic> mutation and significantly associated with a higher risk of death in multivariate analysis adjusted for age, stage and cohort (hazard ratio = 1.78, 95 CI% 1.38\u20132.26, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). <jats:italic>CCNE1<\/jats:italic> high\u2010level amplification combined with overexpression identifies patients with a sufficiently poor prognosis that treatment alternatives are urgently needed. Given that this combination is mutually exclusive to <jats:italic>BRCA1\/2<\/jats:italic> germline mutations, a predictive marker for PARP inhibition, <jats:italic>CCNE1<\/jats:italic> high\u2010level amplification combined with overexpression may serve as a negative predictive test for sensitivity to PARP inhibitors.<\/jats:p>","DOI":"10.1002\/cjp2.168","type":"journal-article","created":{"date-parts":[[2020,5,11]],"date-time":"2020-05-11T06:35:50Z","timestamp":1589178950000},"page":"252-262","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Combined CCNE1 high\u2010level amplification and overexpression is associated with unfavourable outcome in tubo\u2010ovarian high\u2010grade serous carcinoma"],"prefix":"10.1002","volume":"6","author":[{"given":"Angela MY","family":"Chan","sequence":"first","affiliation":[{"name":"Precision Oncology Hub, Department of Oncology University of Calgary, Tom Baker Cancer Centre  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Foothills Medical Center  Calgary AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter F","family":"Rambau","sequence":"additional","affiliation":[{"name":"Department of Pathology Catholic University of Health and Allied Sciences\u2010Bugando  Mwanza Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Grevers","sequence":"additional","affiliation":[{"name":"Department of Cancer Epidemiology and Prevention Research Alberta Health Services\u2010Cancer Control Alberta  Calgary AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald G","family":"Morris","sequence":"additional","affiliation":[{"name":"Precision Oncology Hub, Department of Oncology University of Calgary, Tom Baker Cancer Centre  Calgary AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Neri","sequence":"additional","affiliation":[{"name":"Precision Oncology Hub, Department of Oncology 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